N-(pyridin-2-ylsulfonyl)cyclopropanecarboxamide Derivatives and their Use in the Treatment of Disease

Abstract

The invention relates to heterocyclic compounds of the formula (I), in which all of the variables are as defined in the specification; capable of modulating the activity of CFTR. The invention further provides a method for manufacturing compounds of the invention, and its therapeutic uses. The invention further provides methods to their preparation, to their medical use, in particular to their use in the treatment and management of diseases or disorders including Cystic fibrosis and related disorders.

1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 ring A is pyridinyl or phenyl; 
 ring B is pyridinyl or phenyl; 
 R 1  and R 2  combine to form a C 3-6  cycloalkyl wherein said C 3-6  cycloalkyl is optionally substituted with 1, 2 or 3 halogens; 
 R 3  is —O—R 3′ , —NH—R 3′ , phenyl, pyridyl, C 9-10  heteroaryl, C 3-8  cycloalkyl, C 4-7  heterocycloalkyl, C 6-12  spirocycloalkyl, spirocyclic heterocycle, a 7 to 10 membered fused heterocycle, C 5-6  heterocycloalkene or C 3-6  cycloalkene, wherein said phenyl, pyridyl, C 9-10  heteroaryl, C 3-8  cycloalkyl, C 4-7  heterocycloalkyl, C 6-12  spirocycloalkyl, spirocyclic heterocycle, C 5-6  heterocycloalkene or C 3-6  cycloalkene is optionally substituted with 1 to 4 substituents each independently selected from halogen, CD 3 , C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl, pyridinyl and halo-substituted-C 1-4 alkoxy, or R 3  is C 1-4 alkyl, CD 3 , C 1-5 alkoxy or C 1-4 alkenyl, wherein said C 1-4 alkyl, C 1-4 alkenyl or C 1-4 alkoxy is optionally substituted with 1 to 3 substituents each independently selected from halogen and an optionally substituted phenyl wherein said phenyl is substituted with halo-substituted-C 1-2 alkyl, methyl or 1, 2 or 3 halogens; 
 R 3′  is —C 0-3 alkyl-C 3-8  cycloalkyl, or a fully or partially saturated —C 9-10 bicycloalkyl, wherein said —C 0-3 alkyl-C 3-8  cycloalkyl or fully or partially saturated —C 9-10 bicycloalkyl is optionally substituted with C 1-4 alkyl; 
 R 4  is C 1-4 alkyl, C 1-4 alkoxy, CD 3 , halogen or halo-substituted-C 1-4 alkyl; 
 R 5  is —NR 7 R 8  or R 9 ; 
 R 6  is hydrogen or halogen; 
 R 7  is hydrogen, C 1-6 alkyl, C 3-6  cycloalkyl, C 4-7  heterocycloalkyl, wherein said C 1-6 alkyl, C 3-6  cycloalkyl or C 4-7  heterocycloalkyl is optionally substituted with 1 to 4 substituents each independently selected from deuterium, hydroxy, C 1-4 alkoxy, C 1-4 alkyl and C 3-6  cycloalkyl; 
 R 8  is hydrogen or C 1-4 alkyl; 
 R 9  is a saturated C 4-7  heterocycloalkyl optionally substituted with 1 to 4 substituents each independently selected from deuterium, halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, oxo, nitrile, optionally substituted phenyl, optionally substituted pyridinyl, NHR 11 , —C(O)—R 13 , —C(O)NHR 12 , C 1-4 alkyl-C(O)OR 12  and —C(O)O—R 12 , wherein said optionally substituted phenyl or pyridinyl, is substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino and C 1-4 alkyl, or R 9  is perdeuterated morpholinyl, a 7 to 10 membered fused heterocycle or spirocyclic heterocycle optionally substituted with 1 to 4 substituents each independently selected from deuterium, halogen, hydroxy, C 1-4 alkyl, halo-substituted-C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, oxo, nitrile, C 3-6  cycloalkyl, phenyl, C 4-6  heterocycle, NHR 1 , —S(O) 2 —R 15 , —C(O)—R 13 , —C(O)NHR 11 , C 1-4 alkyl-C(O)OR 12 , —C(O)C 1-3 alkyl-NHR 11  and —C(O)O—R 12 , wherein said phenyl, C 3-6  cycloalkyl and C 4-6  heterocycle are optionally substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino, C 1-4 alkyl, halo-substituted-C 1-4 alkyl and hydroxy-substituted-C 1-4 alkyl; 
 R 11  is hydrogen, C 1-4 alkyl, —C(S)NH—R 15 , —C(O)NH—R 15 , —C(O)R 15  or C 0-3 alkyl-C(O)O—R 14 ; 
 R 12  is hydrogen, C 1-4 alkyl, C 3-6  cycloalkyl or C 1-3 alkyl-C(O)—NHR 14 ; 
 R 13  is C 1-4 alkyl, wherein said alkyl is optionally substituted with amino; 
 R 14  is hydrogen or C 1-4 alkyl; and 
 R 15  is C 3-6  cycloalkyl, phenyl, tolyl or C 1-4 alkyl. 
 
     
     
         2 . The compound of formula (I) of  claim 1 , or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       wherein:
 ring A is pyridinyl or phenyl; 
 ring B is pyridinyl or phenyl; 
 R 1  and R 2  combine to form a C 3-6  cycloalkyl wherein said C 3-6  cycloalkyl is optionally substituted with 1, 2 or 3 halogens; 
 R 3  is —O—C 0-3 alkyl-C 3-8  cycloalkyl-C 0-4 alkyl, —O—C 9-10 bicycloalkyl-C 0-4 alkyl, —NH—C 3-8  cycloalkyl-C 0-4 alkyl, phenyl, pyridyl, C 9-10  heteroaryl, C 3-8  cycloalkyl, C 4-7  heterocycloalkyl, C 6-12  spirocycloalkyl, spirocyclic heterocycle, a 7 to 10 membered fused heterocycle, C 5-6  heterocycloalkene or C 3-6  cycloalkene, wherein said phenyl, pyridyl, C 9-10  heteroaryl, C 3-8  cycloalkyl, C 4-7  heterocycloalkyl, C 6-12  spirocycloalkyl, spirocyclic heterocycle, C 5-6  heterocycloalkene or C 3-6  cycloalkene is optionally substituted with 1 to 4 substituents each independently selected from halogen, CD 3 , C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl, pyridinyl and halo-substituted-C 1-4 alkoxy, or R 3  is C 1-4 alkyl, CD 3 , C 1-5 alkoxy or C 1-4 alkenyl, wherein said C 1-4 alkyl, C 1-4 alkenyl or C 1-4 alkoxy is optionally substituted with 1 to 3 substituents each independently selected from halogen and an optionally substituted phenyl wherein said phenyl is substituted with halo-substituted-C 1-2 alkyl, methyl or 1, 2 or 3 halogens; 
 R 4  is C 1-4 alkyl, C 1-4 alkoxy, CD 3 , halogen or halo-substituted-C 1-4 alkyl; 
 R 5  is —NR 7 R 8  or R 9 ; 
 R 6  is hydrogen or halogen; 
 R 7  is hydrogen, C 1-6 alkyl, C 3-6  cycloalkyl, C 4-7  heterocycloalkyl, wherein said C 1-6 alkyl, C 3-6  cycloalkyl or C 4-7  heterocycloalkyl is optionally substituted with 1 to 4 substituents each independently selected from deuterium, hydroxy, C 1-4 alkoxy, C 1-4 alkyl and C 3-6  cycloalkyl; 
 R 8  is hydrogen or C 1-4 alkyl; 
 R 9  is a saturated C 4-7  heterocycloalkyl optionally substituted with 1 to 4 substituents each independently selected from deuterium, halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, oxo, nitrile, optionally substituted phenyl, optionally substituted pyridinyl, NHR 11 , —C(O)—R 13 , —C(O)NHR 12 , C 1-4 alkyl-C(O)OR 12  and —C(O)O—R 12 , wherein said optionally substituted phenyl or pyridinyl, is substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino and C 1-4 alkyl, or R 9  is perdeuterated morpholinyl, a 7 to 10 membered fused heterocycle or spirocyclic heterocycle optionally substituted with 1 to 4 substituents each independently selected from deuterium, halogen, hydroxy, C 1-4 alkyl, halo-substituted-C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, oxo, nitrile, C 3-6  cycloalkyl, phenyl, C 4-6  heterocycle, NHR 11 , —S(O) 2 —R 15 , —C(O)—R 13 , —C(O)NHR 11 , C 1-4 alkyl-C(O)OR 12 , —C(O)C 1-3 alkyl-NHR 11  and —C(O)O—R 12 , wherein said phenyl, C 3-6  cycloalkyl and C 4-6  heterocycle are optionally substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino, C 1-4 alkyl, halo-substituted-C 1-4 alkyl and hydroxy-substituted-C 1-4 alkyl; 
 R 11  is hydrogen, C 1-4 alkyl, —C(S)NH—R 15 , —C(O)NH—R 15 , —C(O)R 15  or C 0-3 alkyl-C(O)O—R 14 ; 
 R 12  is hydrogen, C 1-4 alkyl, C 3-6  cycloalkyl or C 1-3 alkyl-C(O)—NHR 14 ; 
 R 13  is C 1-4 alkyl, wherein said alkyl is optionally substituted with amino; 
 R 14  is hydrogen or C 1-4 alkyl; and 
 R 15  is C 3-6  cycloalkyl, phenyl, tolyl or C 1-4 alkyl. 
 
     
     
         3 . The compound of  claim 1  having the structure of formula (Ia), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y 1  is N or CH; and 
 Y 2  is CH or N. 
 
     
     
         4 . The compound of  claim 3 , or a pharmaceutically acceptable salt thereof wherein:
 Y 1  is N;   Y 2  is CH;   R 3  is phenyl, pyridyl or C 9-10  heteroaryl, wherein said phenyl, pyridyl or C 9-10  heteroaryl, is optionally substituted with 1 to 4 substituents each independently selected from halogen, CD 3 , C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl and halo-substituted-C 1-4 alkoxy.   
     
     
         5 . The compound of  claim 3 , or a pharmaceutically acceptable salt thereof wherein:
 Y 1  is N;   Y 2  is CH;   R 3  is C 3-8  cycloalkyl, C 4-7  heterocycloalkyl, —O—C 0-3 alkyl-C 3-8  cycloalkyl, C 6-12  spirocycloalkyl, C 5-6  heterocycloalkene or C 3-6  cycloalkene, wherein said C 3-8  cycloalkyl, C 4-7  heterocycloalkyl, C 6-12  spirocycloalkyl, C 5-6  heterocycloalkene or C 3-6  cycloalkene, is optionally substituted with 1 to 4 substituents each independently selected from halogen, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl and halo-substituted-C 1-4 alkoxy.   
     
     
         6 . The compound of  claim 3 , or a pharmaceutically acceptable salt thereof wherein:
 Y 1  is N;   Y 2  is CH;   R 3  is C 1-4 alkyl, CD 3 , C 1-4 alkoxy or C 1-4 alkenyl, wherein said C 1-4 alkyl, C 1-4 alkenyl or C 1-4 alkoxy is optionally substituted with 1 to 3 substituents each independently selected from halogen and an optionally substituted phenyl wherein said phenyl is substituted with halo-substituted-C 1-2 alkyl, methyl or 1, 2 or 3 halogens.   
     
     
         7 . The compound of  claim 3 , or a pharmaceutically acceptable salt thereof wherein:
 Y 1  is N;   Y 2  is N;   R 3  is phenyl, pyridyl or C 9-10  heteroaryl, wherein said phenyl, pyridyl or C 9-10  heteroaryl, is optionally substituted with 1 to 4 substituents each independently selected from halogen, CD 3 , C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl and halo-substituted-C 1-4 alkoxy.   
     
     
         8 . The compound of  claim 3 , or a pharmaceutically acceptable salt thereof wherein:
 Y 1  is N;   Y 2  is N;   R 3  is C 3-8  cycloalkyl, C 4-7  heterocycloalkyl, —O—C 0-3 alkyl-C 3-8  cycloalkyl, C 6-12  spirocycloalkyl, C 5-6  heterocycloalkene or C 3-6  cycloalkene, wherein said C 3-8  cycloalkyl, C 4-7  heterocycloalkyl, C 6-12  spirocycloalkyl, C 5-6  heterocycloalkene or C 3-6  cycloalkene, is optionally substituted with 1 to 4 substituents each independently selected from halogen, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl and halo-substituted-C 1-4 alkoxy.   
     
     
         9 . The compound of  claim 3 , or a pharmaceutically acceptable salt thereof wherein:
 Y 1  is N;   Y 2  is N;   R 3  is C 1-4 alkyl, CD 3 , C 1-4 alkoxy or C 1-4 alkenyl, wherein said C 1-4 alkyl, C 1-4 alkenyl or C 1-4 alkoxy is optionally substituted with 1 to 3 substituents each independently selected from halogen and an optionally substituted phenyl wherein said phenyl is substituted with halo-substituted-C 1-2 alkyl, methyl or 1, 2 or 3 halogens.   
     
     
         10 . The compound of  claim 3 , or a pharmaceutically acceptable salt thereof, wherein:
 R 6  is hydrogen.   
     
     
         11 . The compound of  claim 3 , or a pharmaceutically acceptable salt thereof, wherein:
 R 6  is fluoro or chloro.   
     
     
         12 . The compound of  claim 3  having the structure of formula (Ib) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 3  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         X is CH or N; 
         R 4  is CH 3 , CD 3 , —OCH 3 , Cl, F or CF 3 ; 
         R 5  is R 9 ; 
         R 9  is a saturated C 4-7  heterocycloalkyl optionally substituted with 1 to 4 substituents each independently selected from deuterium, halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, oxo, nitrile, optionally substituted phenyl, NHR 11 , —C(O)NHR 12 , C 1-4 alkyl-C(O)OR 12  and —C(O)O—R 12 , wherein said optionally substituted phenyl, is substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino and C 1-4 alkyl; 
         R 11  is hydrogen, C 1-4 alkyl, —C(O)NH—R 15 , —C(O)R 15  or C 0-3 alkyl-C(O)O—R 14 ; 
         R 12  is hydrogen, C 1-4 alkyl, C 3-6  cycloalkyl or C 1-3 alkyl-C(O)—NHR 14 ; 
         R 14  is hydrogen or C 1-4 alkyl; 
         R 15  is C 3-6  cycloalkyl, tolyl or C 1-4 alkyl; 
         R 16  is selected from hydrogen, CD 3 , halogen, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl and halo-substituted-C 1-4 alkoxy; 
         R 17  is selected from hydrogen, CD 3 , halogen, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl and halo-substituted-C 1-4 alkoxy; and 
         R 18  is selected from hydrogen and halogen. 
       
     
     
         13 . The compound of  claim 3  having the structure of formula (Ib), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 3  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         Z is CH 2  or O; 
         R 4  is CH 3 , CD 3 , —OCH 3 , Cl, F or CF 3 ; 
         R 5  is R 9 ; 
         R 9  is a saturated C 4-7  heterocycloalkyl optionally substituted with 1 to 4 substituents each independently selected from deuterium, halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, oxo, nitrile, optionally substituted phenyl, NHR 11 , —C(O)NHR 12 , C 1-4 alkyl-C(O)OR 12  and —C(O)O—R 12 , wherein said optionally substituted phenyl, is substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino and C 1-4 alkyl; 
         R 11  is hydrogen, C 1-4 alkyl, —C(O)NH—R 15 , —C(O)R 15  or C 0-3 alkyl-C(O)O—R 14 ; 
         R 12  is hydrogen, C 1-4 alkyl, C 3-6  cycloalkyl or C 1-3 alkyl-C(O)—NHR 14 ; 
         R 14  is hydrogen or C 1-4 alkyl; 
         R 15  is C 3-6  cycloalkyl, tolyl or C 1-4 alkyl; 
         R 19  is selected from hydrogen, C 1-4 alkyl, halo-substituted-C 1-4 alkyl and halogen; 
         R 20  is selected from hydrogen, C 1-4 alkyl and halogen; or R 19  and R 20  may combine to form an optionally substituted C 3-6  cycloalkyl or C 4-6  heterocycloalkyl ring; and 
         R 21  is selected from hydrogen, C 1-4 alkyl, halo-substituted-C 1-4 alkyl and halogen. 
       
     
     
         14 . The compound of  claim 3  having the structure of formula (Ic), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 4  is CH 3 , CD 3 , —OCH 3 , Cl, F or CF 3 ; 
 R 5  is R 9 ; 
 R 9  is a saturated C 4-7  heterocycloalkyl optionally substituted with 1 to 4 substituents each independently selected from deuterium, halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, oxo, nitrile, optionally substituted phenyl, NHR 11 , —C(O)NHR 12 , C 1-4 alkyl-C(O)OR 12  and —C(O)O—R 12 , wherein said optionally substituted phenyl, is substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino and C 1-4 alkyl; 
 R 11  is hydrogen, C 1-4 alkyl, —C(O)NH—R 15 , —C(O)R 15  or C 0-3 alkyl-C(O)O—R 14 ; 
 R 12  is hydrogen, C 1-4 alkyl, C 3-6  cycloalkyl or C 1-3 alkyl-C(O)—NHR 14 ; 
 R 14  is hydrogen or C 1-4 alkyl; 
 R 15  is C 3-6  cycloalkyl, tolyl or C 1-4 alkyl; 
 R 16  is selected from hydrogen, CD 3 , halogen, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl and halo-substituted-C 1-4 alkoxy; and 
 R 17  is selected from hydrogen, CD 3 , halogen, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl and halo-substituted-C 1-4 alkoxy. 
 
     
     
         15 . The compound of  claim 13  having the structure of formula (Id), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 Z is CH 2  or O; 
 R 4  is CH 3 , CD 3 , —OCH 3 , Cl, F or CF 3 ; 
 R 5  is R 9 ; 
 R 9  is a saturated C 4-7  heterocycloalkyl optionally substituted with 1 to 4 substituents each independently selected from deuterium, halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, oxo, nitrile, optionally substituted phenyl, NHR 11 , —C(O)NHR 12 , C 1-4 alkyl-C(O)OR 12  and —C(O)O—R 12 , wherein said optionally substituted phenyl, is substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino and C 1-4 alkyl; 
 R 11  is hydrogen, C 1-4 alkyl, —C(O)NH—R 15 , —C(O)R 15  or C 0-3 alkyl-C(O)O—R 14 ; 
 R 12  is hydrogen, C 1-4 alkyl, C 3-6  cycloalkyl or C 1-3 alkyl-C(O)—NHR 14 ; 
 R 14  is hydrogen or C 1-4 alkyl; 
 R 15  is C 3-6  cycloalkyl, tolyl or C 1-4 alkyl; 
 R 19  is selected from hydrogen, C 1-4 alkyl, halo-substituted-C 1-4 alkyl and halogen; 
 R 20  is selected from hydrogen, C 1-4 alkyl and halogen; or R 19  and R 20  may combine to form an optionally substituted C 3-6  cycloalkyl or C 4-6  heterocycloalkyl ring; and 
 R 21  is selected from hydrogen, C 1-4 alkyl, halo-substituted-C 1-4 alkyl and halogen. 
 
     
     
         16 . The compound of  claim 13  having the structure of formula (Ie), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 4  is CH 3 , CD 3 , —OCH 3 , Cl, F or CF 3 ; 
 R 5  is R 9 ; 
 R 9  is a saturated C 4-7  heterocycloalkyl optionally substituted with 1 to 4 substituents each independently selected from deuterium, halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, oxo, nitrile, optionally substituted phenyl, NHR 11 , —C(O)NHR 12 , C 1-4 alkyl-C(O)OR 12  and —C(O)O—R 12 , wherein said optionally substituted phenyl, is substituted with 1 to 3 substituents each independently selected from hydroxy, halogen, amino and C 1-4 alkyl; 
 R 11  is hydrogen, C 1-4 alkyl, —C(O)NH—R 15 , —C(O)R 15  or C 0-3 alkyl-C(O)O—R 14 ; 
 R 12  is hydrogen, C 1-4 alkyl, C 3-6  cycloalkyl or C 1-3 alkyl-C(O)—NHR 14 ; 
 R 14  is hydrogen or C 1-4 alkyl; 
 R 15  is C 3-6  cycloalkyl, tolyl or C 1-4 alkyl; 
 R 19  is selected from hydrogen, C 1-4 alkyl, halo-substituted-C 1-4 alkyl and halogen; 
 R 20  is selected from hydrogen, C 1-4 alkyl and halogen; or R 19  and R 20  may combine to form an optionally substituted C 3-6  cycloalkyl or C 4-6  heterocycloalkyl ring; and 
 R 21  is selected from hydrogen, C 1-4 alkyl, halo-substituted-C 1-4 alkyl and halogen. 
 
     
     
         17 . The compound of  claim 14 , or a pharmaceutically acceptable salt thereof, wherein:
 R 4  is CD 3 , CH 3 , Cl, CF 3  or F.   
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The compound of  claim 14 , or a pharmaceutically acceptable salt thereof, wherein:
 R 5  is R 9 ; and   R 9  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         R 22  is hydrogen, deuterium, chloro, fluoro, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl or hydroxy-substituted-C 1-4 alkyl; and 
         R 23  is hydrogen, chloro, fluoro, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl or hydroxy-substituted-C 1-4 alkyl; or R 22  and R 23  may combine to form oxo. 
       
     
     
         22 . The compound of  claim 1 , selected from the group consisting of:
 N-((6-Aminopyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropane-1-carboxamide;   N-((6-Aminopyridin-2-yl)sulfonyl)-1-((3′-fluoro-5′-isobutoxy-4-methyl-[1,1′-biphenyl]-2-yl)oxy)cyclopropane-1-carboxamide;   N-((6-aminopyridin-2-yl)sulfonyl)-1-(5-methyl-2-(2-(trifluoromethyl)cyclopropyl)phenoxy)cyclopropane-1-carboxamide;   N-((6-Aminopyridin-2-yl)sulfonyl)-1-(2-(4,4-difluorocyclohexyl)-5-methylphenoxy)cyclopropane-1-carboxamide;   N-((6-Aminopyridin-2-yl)sulfonyl)-1-(2-(3,3-difluorocyclohexyl)-5-methylphenoxy)cyclopropane-1-carboxamide;   N-((6-Aminopyridin-2-yl)sulfonyl)-1-(2-cycloheptyl-5-methylphenoxy)cyclopropane-1-carboxamide;   N-((6-Amino-3-fluoropyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropane-1-carboxamide;   N-((6-Aminopyridin-2-yl)sulfonyl)-1-(5-methyl-2-(1-(trifluoromethyl)cyclopropyl)phenoxy)cyclopentane-1-carboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(3-hydroxyazetidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   (S)-1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(3-methylmorpholino)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   Methyl 1-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylate;   Methyl 1-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropane-1-carbonyl)sulfamoyl)pyridin-2-yl)piperidine-4-carboxylate;   1-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid;   1-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)piperidine-4-carboxylic acid;   Cyclopentyl 1-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)piperidine-4-carboxylate;   Tert-butyl (1-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)-4-methylpiperidin-4-yl)carbamate;   N-((6-(4-Amino-4-methylpiperidin-1-yl)pyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(4-(cyclopropanecarboxamido)-4-methylpiperidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(4-(3-cyclopropylureido)-4-methylpiperidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   Tert-butyl (1-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)piperidin-3-yl)carbamate;   N-((6-(3-Aminopiperidin-1-yl)pyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarboxamide;   1-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)-4-methylpiperidine-4-carboxamide;   N-((6-(4-Cyano-4-methylpiperidin-1-yl)pyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   N-((6-(4-Amino-4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(3-methoxyazetidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   N-((6-(4-Amino-4-(fluoromethyl)piperidin-1-yl)pyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarboxamide;   N-((6-(1-Amino-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarboxamide;   N-((6-(1,6-Diazaspiro[3.3]heptan-6-yl)pyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarboxamide;   Tert-butyl (1-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)carbamate;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(4-(3-cyclopropylthioureido)-4-methylpiperidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   Tert-butyl (1-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)carbamate;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(dimethylamino)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   (R)-1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(3-methylmorpholino)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   N-((6-(3-Amino-3-methylpyrrolidin-1-yl)pyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(6-fluoro-4-oxospiro[chroman-2,4′-piperidin]-1′-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   Tert-butyl 6-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate;   Tert-butyl 6-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)-1,6-diazaspiro[3.3]heptane-1-carboxylate;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(piperazin-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   N-((6-(1-Amino-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarboxamide;   N-((6-(1-Amino-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(3-oxopiperazin-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   Tert-butyl 4-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)piperazine-1-carboxylate;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-((trans-3-hydroxycyclobutyl)amino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-((cis-3-hydroxycyclobutyl)amino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(3-(trifluoromethyl)piperazin-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   Methyl 3-(4-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)piperazin-1-yl)-2,2-dimethylpropanoate;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(morpholino-d 8 )pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(5-oxo-1,4-diazepan-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   N-((6-(4-Aminopiperidin-1-yl)pyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarboxamide;   Tert-butyl (1-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)-4-(fluoromethyl)piperidin-4-yl)carbamate;   Tert-butyl (1-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropanecarbonyl)sulfamoyl)pyridin-2-yl)piperidin-4-yl)carbamate;   N-((6-(5-cis-amino-3-azabicyclo[4.1.0]heptan-3-yl)pyridin-2-yl)sulfonyl)-1-(2-cyclohexyl-5-methylphenoxy)cyclopropane-1-carboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-((2-hydroxypropyl)amino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (R)-1-(2-cyclohexyl-5-methylphenoxy)-N-((6-((2-hydroxypropyl)amino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)-1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-((2-hydroxypropyl)amino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-((2-hydroxypropyl)(methyl)amino)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   Tert-butyl (1-(6-(N-(1-(2-cyclohexyl-5-methylphenoxy)cyclopropane-1-carbonyl)sulfamoyl)pyridin-2-yl)-3-methylazetidin-3-yl)carbamate;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(2-methylmorpholino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)-1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(2-methylmorpholino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (R)-1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(2-methylmorpholino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(4-phenylpiperazin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(4-(4-fluorophenyl)piperazin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-Cyclohexyl-5-methylphenoxy)-N-((6-(6-tosyl-1,6-diazaspiro[3.3]heptan-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(5-Chloro-2-cyclohexylphenoxy)-N-((6-(3-hydroxyazetidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-(4,4-Difluorocyclohexyl)-5-methylphenoxy)-N-((6-(6′-fluoro-4′-oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-quinolin]-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   (S)-1-(2-(4,4-Difluorocyclohexyl)-5-fluorophenoxy)-N-((6-((1-hydroxypropan-2-yl)amino)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   (S)-1-(2-(4,4-Difluorocyclohexyl)-5-methylphenoxy)-N-((6-(3-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (R)-1-(2-(4,4-Difluorocyclohexyl)-5-methylphenoxy)-N-((6-(3-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (R)-1-(2-(4,4-Difluorocyclohexyl)-5-methylphenoxy)-N-((6-((2-hydroxypropyl)amino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (R)-1-(2-(4,4-Difluorocyclohexyl)-5-methylphenoxy)-N-((6-((1-hydroxypropan-2-yl)amino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   Tert-butyl (1-(6-(N-(1-(2-(4,4-difluorocyclohexyl)-5-methylphenoxy)cyclopropane-1-carbonyl)sulfamoyl)pyridin-2-yl)-3-methylazetidin-3-yl)carbamate;   (S)-1-(2-(4,4-Difluorocyclohexyl)-5-methoxyphenoxy)-N-((6-(3-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-(Trans-4-fluorocyclohexyl)-5-methylphenoxy)-N-((6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)-1-(2,5-Dimethylphenoxy)-N-((6-(3-methylmorpholino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-(3,3-Difluorocyclobutyl)-5-methylphenoxy)-N-((6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   (R)-1-(2,5-dimethylphenoxy)-N-((6-((2-hydroxypropyl)amino)pyridin-2-yl)sulfonyl)cyclopentane-1-carboxamide;   (S)-1-(2-Cyclopentyl-5-methylphenoxy)-N-((6-((2-hydroxypropyl)amino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (R)-1-(2-Cyclopentyl-5-methylphenoxy)-N-((6-((2-hydroxypropyl)amino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-(3,3-Difluorocyclopentyl)-5-methylphenoxy)-N-((6-((R)-3-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (R)—N-((6-(3-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)sulfonyl)-1-(2-isobutyl-5-methylphenoxy)cyclopropane-1-carboxamide;   (S)—N-((6-((2-Hydroxypropyl)amino)pyridin-2-yl)sulfonyl)-1-(2-isobutyl-5-methylphenoxy)cyclopropane-1-carboxamide;   (R)—N-((6-((2-Hydroxypropyl)amino)pyridin-2-yl)sulfonyl)-1-(2-isobutyl-5-methylphenoxy)cyclopropane-1-carboxamide;   (S)-1-(5-Chloro-2-isobutylphenoxy)-N-((6-((2-hydroxypropyl)amino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(5-Chloro-2-(spiro[2.5]octan-6-yl)phenoxy)-N-((6-(3-hydroxyazetidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (R)-1-(5-Chloro-2-(4,4-dimethylcyclohexyl)phenoxy)-N-((6-(2-methylmorpholino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)-1-(2-Cyclopropyl-5-methylphenoxy)-N-((6-((2-hydroxypropyl)amino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)-1-(5-Chloro-2-cyclopropylphenoxy)-N-((6-((2-hydroxypropyl)amino)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)—N-((6-((2-Hydroxypropyl)amino)pyridin-2-yl)sulfonyl)-1-(5-methyl-2-(1-methylcyclopropyl)phenoxy)cyclopropane-1-carboxamide;   N-((6-(3-Hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)sulfonyl)-1-(5-methyl-2-(1-(trifluoromethyl)cyclopropyl)phenoxy)cyclopropane-1-carboxamide;   1-(5-Fluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)phenoxy)-N-((6-(4-phenylpiperazin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)—N-((6-(3-Hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)-1-(5-methyl-2-(spiro[3.3]heptan-2-yl)phenoxy)cyclopropane-1-carboxamide;   N-((6-((R)-3-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)sulfonyl)-1-(5-methyl-2-(tetrahydro-2H-pyran-3-yl)phenoxy)cyclopropane-1-carboxamide;   (R)-1-(2-(3,4-Dihydro-2H-pyran-5-yl)-5-methylphenoxy)-N-((6-(3-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   N-((6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)sulfonyl)-1-((4-methyl-1′,2′,3′,6′-tetrahydro-[1,1′-biphenyl]-2-yl)oxy)cyclopropanecarboxamide;   1-(2-(cis-4-fluorocyclohexyl)-5-methylphenoxy)-N-((6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-(6,6-Dimethyltetrahydro-2H-pyran-3-yl)-5-methylphenoxy)-N-((6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-((S)-6,6-dimethyltetrahydro-2H-pyran-3-yl)-5-methylphenoxy)-N-((6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-(2-((R)-6,6-dimethyltetrahydro-2H-pyran-3-yl)-5-methylphenoxy)-N-((6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)—N-((6-(3-Hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)-1-((4-methyl-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)oxy)cyclopropane-1-carboxamide;   (S)-1-((4-Chloro-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)oxy)-N-((6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   1-((4-Chloro-3′-isobutoxy-[1,1′-biphenyl]-2-yl)oxy)-N-((6-(4-cyano-4-methylpiperidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)-1-(2-(Benzofuran-6-yl)-5-chlorophenoxy)-N-((6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)-1-((3′,4-Bis(trifluoromethyl)-[1,1′-biphenyl]-2-yl)oxy)-N-((6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)-1-((4-Chloro-3′-(trifluoromethoxy)-[1,1′-biphenyl]-2-yl)oxy)-N-((6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)-1-((4-Chloro-4′-fluoro-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)oxy)-N-((6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   N-((6-(3-Hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)sulfonyl)-1-((4-methyl-3′-(trifluoromethoxy)-[1,1′-biphenyl]-2-yl)oxy)cyclopropane-1-carboxamide;   (S)-1-((3′-(Difluoromethyl)-4-methyl-[1,1′-biphenyl]-2-yl)oxy)-N-((6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)—N-((6-(3-Hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)-1-((4-methyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)oxy)cyclopropane-1-carboxamide;   (R)—N-((6-(3-Hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)-1-((4-methyl-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)oxy)cyclopropane-1-carboxamide;   (S)-1-(2-(Benzofuran-5-yl)-5-chlorophenoxy)-N-((6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   (S)—N-((6-(3-Hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)-1-(5-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)phenoxy)cyclopropane-1-carboxamide;   (S)—N-((6-(3-Hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)-1-((4-methyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)oxy)cyclopropane-1-carboxamide;   (S)-1-(5-Chloro-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)phenoxy)-N-((6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   N-((6-(4-Amino-4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)sulfonyl)-1-((4-methyl-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)oxy)cyclopropane-1-carboxamide;   (S)-1-(2-(Benzyloxy)-5-methylphenoxy)-N-((6-(2-methylmorpholino)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide;   N-((6-(4-Cyano-4-methylpiperidin-1-yl)pyridin-2-yl)sulfonyl)-1-(2-(cyclopentyloxy)-5-methylphenoxy)cyclopropanecarboxamide; and   (S)-1-(2-(Cyclohexyloxy)-5-methylphenoxy)-N-((6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropane-1-carboxamide;   or a pharmaceutically acceptable salt thereof.   
     
     
         23 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, or diluent. 
     
     
         24 . The pharmaceutical composition of  claim 23 , further comprising one or more additional pharmaceutical agent(s). 
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein the additional pharmaceutical agent(s) is selected from a mucolytic agent, nebulized hypertonic saline, bronchodilator, an antibiotic, an anti-infective agent, a CFTR modulator and an anti-inflammatory agent. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . The pharmaceutical composition of  claim 24 , wherein the additional pharmaceutical agents are a CFTR modulator and a CFTR potentiator. 
     
     
         30 . A method for treating a CFTR mediated disease in a subject comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof of  claim 1 . 
     
     
         31 . The method of  claim 30 , wherein the CFTR mediated disease is selected from cystic fibrosis, asthma, COPD, emphysema and chronic bronchitis. 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . The method of  claim 30 , further comprising administering to the subject one or more additional pharmaceutical agent(s) prior to, concurrent with, or subsequent to the compound of  claim 1 . 
     
     
         35 . The method of  claim 34 , wherein the additional pharmaceutical agent(s) is selected from a mucolytic agent, nebulized hypertonic saline, bronchodilator, an antibiotic, an anti-infective agent, a CFTR modulator and an anti-inflammatory agent. 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 34 , wherein the additional pharmaceutical agents are a CFTR modulator and a CFTR potentiator. 
     
     
         39 . The compound of  claim 15 , or a pharmaceutically acceptable salt thereof, wherein:
 R 4  is CD 3 , CH 3 , Cl, CF 3  or F.   
     
     
         40 . The compound of  claim 15 , or a pharmaceutically acceptable salt thereof, wherein:
 R 5  is R 9 ; and   R 9  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         R 22  is hydrogen, deuterium, chloro, fluoro, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl or hydroxy-substituted-C 1-4 alkyl; and 
         R 23  is hydrogen, chloro, fluoro, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl or hydroxy-substituted-C 1-4 alkyl; or R 22  and R 23  may combine to form oxo. 
       
     
     
         41 . The compound of  claim 16 , or a pharmaceutically acceptable salt thereof, wherein:
 R 4  is CD 3 , CH 3 , Cl, CF 3  or F.   
     
     
         42 . The compound of  claim 16 , or a pharmaceutically acceptable salt thereof, wherein:
 R 5  is R 9 ; and   R 9  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         R 22  is hydrogen, deuterium, chloro, fluoro, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl or hydroxy-substituted-C 1-4 alkyl; and 
         R 23  is hydrogen, chloro, fluoro, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkyl or hydroxy-substituted-C 1-4 alkyl; or R 22  and R 23  may combine to form oxo.